The overall objective of this proposal is to determine the role of apoptosis in HIV-1 dementia. We and others previously demonstrated apoptosis of neurons and other cell types in brain from patients with HIV-1 dementia, indicating that apoptosis is likely to contribute to neuronal loss and cognitive dysfunction in AIDS. We have shown that infection of primary human brain cultures by particular HIV-1 isolates induces neuronal apoptosis. Our studies suggest that the HIV-1 Env is an important determinant of neurodegenerative mechanisms associated with HIV-1 infection and further suggest that certain X4 or R5X4 viruses which emerge in the late stages of disease may impact disease progression in the CNS. The mechanisms that lead to neuronal apoptosis in the brain of AIDS patients in vivo have not been identified. This proposal will address several questions that are important for understanding mechanisms which lead to apoptosis to HIV-1 in dementia. Aim 1 will characterize HIV-1 viruses in brain, CSF, and blood that induce neuronal and determine their correlation with clinical dementia. The role of HIV-1 Envs cloned directly from brain and other tissues in mechanisms. In mechanisms that lead to neuronal apoptosis will also be investigated. Aim 2 will investigate the role of HIV-1 gp120 interactions with CXCR4 and other chemokine receptors in mechanisms that lead to neuronal apoptosis. Aim 3 will characterize the phenotype and function of two distinct populations of microglia which differentially express CCR5 and CCR3. We will then determine their relative susceptibility to HIV-1 infection, signaling induced by HIV-1 gp120 and chemokines, and production of soluble factors that induce neuronal apoptosis. These studies will establish in vitro assays for HIV-1 neuropathogenicity which will lead to a better understanding of mechanisms of apoptosis and CNS injury in HIV-1 dementia and help to advance the development of new therapeutic strategies. These studies may also provide insights relevant for mechanisms involved in other neurodegenerative diseases.